Research ArticleAlzheimer’s Disease

Familial Alzheimer’s disease–associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry

Sci. Signal.  06 Sep 2016:
Vol. 9, Issue 444, pp. ra89
DOI: 10.1126/scisignal.aaf1371

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Cleaving toward memory loss

The senile dementia that occurs in Alzheimer’s disease is devastating for patients and their families. Neuronal shape dictates learning and memory, and neurons from mouse models of Alzheimer’s disease show altered neuronal morphology and dysregulated Ca2+ signaling. Tong et al. found that the endoplasmic reticulum Ca2+ sensor STIM1 was subjected to excess cleavage and inactivation by forms of presenilin 1 (PS1) with familial Alzheimer’s disease–associated mutations. Hippocampal neurons expressing a mutant PS1 showed dysregulated Ca2+ signaling and altered neuronal morphology, both of which were rescued by inhibiting cleavage by PS1 or overexpressing STIM1. Thus, the cleavage of STIM1 by PS1 may contribute to the memory loss that is characteristic of Alzheimer’s disease.

Abstract

Some forms of familial Alzheimer’s disease (FAD) are caused by mutations in presenilins (PSs), catalytic components of a γ-secretase complex that cleaves target proteins, including amyloid precursor protein (APP). Calcium (Ca2+) dysregulation in cells with these FAD-causing PS mutants has been attributed to attenuated store-operated Ca2+ entry [SOCE; also called capacitative Ca2+ entry (CCE)]. CCE occurs when STIM1 detects decreases in Ca2+ in the endoplasmic reticulum (ER) and activates ORAI channels to replenish Ca2+ stores in the ER. We showed that CCE was attenuated by PS1-associated γ-secretase activity. Endogenous PS1 and STIM1 interacted in human neuroblastoma SH-SY5Y cells, patient fibroblasts, and mouse primary cortical neurons. Forms of PS1 with FAD-associated mutations enhanced γ-secretase cleavage of the STIM1 transmembrane domain at a sequence that was similar to the γ-secretase cleavage sequence of APP. Cultured hippocampal neurons expressing mutant PS1 had attenuated CCE that was associated with destabilized dendritic spines, which were rescued by either γ-secretase inhibition or overexpression of STIM1. Our results indicate that γ-secretase activity may physiologically regulate CCE by targeting STIM1 and that restoring STIM1 may be a therapeutic approach in AD.

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